Small-molecule degron mimetics for targeted protein degradation

More than 80% of intracellular proteins are degraded by the ubiquitin-proteasome system. This system relies on a cascade of enzymes-E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase)-to catalyze the polyubiquitination of target proteins, which are then recognized and degraded by the 26S proteasome. Among these enzymes, E3 ubiquitin ligases play a central role by specifically recognizing degron motifs on substrate proteins. The presence and accessibility of these degrons often dictate the half-life and stability of a given protein. Leveraging this mechanism, the artificial introduction of degrons or degron mimetics into otherwise stable proteins has emerged as a novel strategy in drug discovery for selectively degrading disease-causing proteins. In this short review, I will highlight small-molecule degron mimetics that have been developed for targeted protein degradation.